Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 148, Issue 10, Pages 2594-2607Publisher
WILEY
DOI: 10.1002/ijc.33477
Keywords
ApcMin; mice; CCR2; IL8208; 17; intestinal tumorigenesis
Categories
Funding
- National Cancer Institute [R01CA138623, R21CA216090]
- National Institute of General Medical Sciences [P20GM125504-01]
- National Institutes of Health/National Cancer Institute [5R21CA191683]
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The CCL2/CCR2 axis plays a crucial role in the development of spontaneous intestinal tumorigenesis, with CCR2(-/-)Apc(Min/+) mice showing increased overall survival and reduced tumor burden. These mice also showed decreased myeloid cell population and increased IFN-gamma producing T cells. Tumors in CCR2(-/-)Apc(Min/+) mice exhibited reduced IL-17 and IL-23 levels but increased IFN-gamma and Granzyme B levels compared to Apc(Min/+) tumors.
The biological activities of chemokine (C-C motif) ligand 2 (CCL2) are mediated via C-C chemokine receptor-2 (CCR2). Increased CCL2 level is associated with metastasis of many cancers. In our study, we investigated the role of the CCL2/CCR2 axis in the development of spontaneous intestinal tumorigenesis using the Apc(Min/+) mouse model. Ablation of CCR2 in Apc(Min/+) mice significantly increased the overall survival and reduced intestinal tumor burden. Immune cell analysis showed that CCR2(-/-)Apc(Min/+) mice exhibited significant reduction in the myeloid cell population and increased interferon gamma (IFN-gamma) producing T cells both in spleen and mesenteric lymph nodes compared to Apc(Min/+) mice. The CCR2(-/-)Apc(Min/+) tumors showed significantly reduced levels of interleukin (IL)-17 and IL-23 and increased IFN-gamma and Granzyme B compared to Apc(Min/+) tumors. Transfer of CCR2(+/+)Apc(Min/+) CD4(+) T cells into Rag2(-/-) mice led to development of colitis phenotype with increased CD4(+) T cells hyper proliferation and IL-17 production. In contrast, adoptive transfer of CCR2(-/-)Apc(Min/+) CD4(+) T cells into Rag2(-/-) mice failed to enhance colonic inflammation or IL-17 production. These results a suggest novel additional role for CCR2, where it regulates migration of IL-17 producing cells mediating tumor-promoting inflammation in addition to its role in migration of tumor associated macrophages.
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